Highly concentrated stable meloxicam solutions

ABSTRACT

Aqueous cyclodextrin-free solution of meloxicam for administration by oral or parenteral route, containing a pharmacologically acceptable meloxicam salt of an organic or inorganic base and one or more suitable excipients, the content of dissolved meloxicam salt being more than 10 mg/mL. The formulation according to the invention has a shelf-life of up to 24 months or more.

The present invention relates to highly concentrated stable meloxicamsolutions for oral and parenteral administration, particularly fortreating respiratory diseases in large farm animals.

BACKGROUND OF THE INVENTION

Meloxicam(4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide)is an active substance which belongs to the group of NSAIDs(non-steroidal antiinflammatory drugs). Meloxicam and the sodium andmeglumine (N-methyl-D-glucamine) salt thereof are described in EP-A-0002 482. EP-A-0 002 482 shows, inter alia, the example of a 0.2%injectable solution of meloxicam consisting of the meglumine salt of theactive substance, sodium chloride, and water.

EP-A-0 945 134 discloses the pH-dependent solubility characteristics ofmeloxicam and its salts, i.e., the sodium salt, the ammonium salt, andthe meglumine salt, in aqueous solution. According to EP-A-0 945 134,meloxicam is an active substance which does not dissolve readily inwater and the meloxicam salts, particularly the meglumine salt, exhibitimproved solubility as the pH increases between 4 and 10, as shown inTable 1 of EP-0 945 134. However, until now it has only been possible toproduce stable, clear, aqueous solutions with a low concentration ofmeloxicam. In addition to involving the in situ formation of a meloxicamsalt, e.g., meglumine salt, and the addition of solubilizers, theseprior art solutions were required to have a pH in the range of maximumpossible solubility as well as being reasonably well-tolerated andcontain a high proportion of organic solvent. Formulation tests with thesame or a similar recipe led to cloudiness of the solution if themeloxicam concentrations were higher, e.g., 2%.

WO9959634 A1 describes an eye drop solution containing 0.5% meloxicambut makes no reference to possible meloxicam concentrations over 1%. Forexample, a commercially available 0.5% meloxicam solution is used insmall animals such as dogs, heifers, and calves to treat respiratorydiseases.

Thus, it has not hitherto been possible to treat large farm animals withan injectable meloxicam solution as the low concentration of activesubstance in the injectable solution did not allow an acceptable,well-tolerated injection volume due to the great weight of the animals.Furthermore, parenteral administration requires that the solution befree from particles; if there are particles in a parenteral drug, thereis a risk of vascular damage or embolism. Moreover, organic solvents,solubilizers, and water-soluble substances can only be used in certainconcentrations to achieve acceptable drug tolerance. These problems aresolved by the present invention which provides particle-free, highlyconcentrated meloxicam solutions which are stable over long periods andsuitable for treating farm animals up to 750 kg in weight. The meloxicamsolutions of the present invention should, therefore, be suitable foradministration both orally or parenterally.

DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that highly concentrated meloxicamsolutions which contain, in addition to a meloxicam salt and certainexcipients, another excipient selected from among citric acid, lecithin,gluconic acid, tartaric acid, phosphoric acid, and EDTA or the saltsthereof, may be produced so as to be particle-free and stable over longperiods. The stability was achieved with an unexpectedly small amount oforganic solubilizers. The formulation was found to be stable even whensubjected to the process of final sterilization.

This results in the solution to the problem according to the invention,as a formulation of a meloxicam solution which contains, in addition toa meloxicam salt, small concentrations of solubilizer, a preservative, abuffer substance for achieving the optimum pH range, and anotherexcipient.

The invention relates to aqueous cyclodextrin-free solutions ofmeloxicam for parenteral or oral administration which contain apharmacologically acceptable meloxicam salt of an organic or inorganicbase in a highly concentrated solution with 11-25 mg/mL of meloxicamtogether with suitable excipients.

The formulation according to the invention overcomes the problem arisingfrom the prior art of providing an injectable solution of the activesubstance meloxicam which is also suitable for treating large farmanimals, by permitting a high concentration of active substance in aparticle free solution which is stable over the long term, having thecomposition described hereinafter.

The formulation according to the invention may contain, as the meloxicamsalt, the meglumine, sodium, potassium, or ammonium salt, preferably themeloxicam meglumine salt.

The solubilizers used may be, for example, polyethyleneglycols,polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer 188),glycofurol, arginine, lysine, castor oil, propyleneglycol, solketal,polysorbate, glycerol, sorbitol, mannitol, xylitol,polyvinylpyrrolidone, lecithin, cholesterol, 12-hydroxystearicacid-PEG660-ester, propyleneglycol monostearate, polyoxy-40-hydrogenatedcastor oil, polyoxyl-10-oleyl-ether, polyoxyl-20-cetostearylether, andpolyoxyl-40-stearate or a mixture of sorbitol, mannitol and xylitol,preferably polyethyleneglycols, polyoxyethylene-polyoxypropylenecopolymers, glycofurol, polyvinylpyrrolidone, lecithin, cholesterol,12-hydroxystearic acid-PEG66O-esters, propyleneglycol monostearate,polyoxy-40-hydrogenated castor oil, polyoxyl-10-oleyl-ether,polyoxyl-20-cetostearylether, and polyoxyl-40-stearate. Particularlypreferred are polyethyleneglycols, glycofurol, andpolyoxyethylene-polyoxypropylene-copolymers, but especiallypolyethyleneglycols (e.g., Macrogol 300) andpolyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer 188). Thepreservatives used may be, for example, ethanol, benzoic acid and thesodium or potassium salts thereof, sorbic acid and the sodium orpotassium salts thereof, chlorobutanol, benzyl alcohol, phenylethanol,the methyl, ethyl, propyl, or butyl p-hydroxybenzoates, phenol,m-cresol, p-chloro-m-cresol, or benzalkonium chloride. Particularlypreferred are ethanol, benzoic acid and the sodium or potassium saltsthereof, sorbic acid and the sodium or potassium salts thereof,chlorobutanol, benzyl alcohol, phenylethanol, and the methyl, ethyl,propyl, or butyl p-hydroxybenzoates, but preferably ethanol, benzoicacid and the sodium or potassium salts thereof, sorbic acid and thesodium or potassium salts thereof, but especially ethanol.

The buffer system used to achieve a pH of between 8 and 10 may be, forexample, glycine, a mixture of glycine and HCl, a mixture of glycine andsodium hydroxide solution, and the sodium and potassium salts thereof, amixture of potassium hydrogen phthalate and hydrochloric acid, a mixtureof potassium hydrogen phthalate and sodium hydroxide solution, or amixture of glutamic acid and glutamate. Glycine, a mixture of glycineand HCl, and a mixture of glycine/sodium hydroxide solution, especiallyglycine, are particularly preferred.

Other suitable excipients are citric acid, lecithin, gluconic acid,tartaric acid, phosphoric acid, and EDTA or the alkali metal saltsthereof, preferably tartaric acid and EDTA or the alkali metal saltsthereof, particularly disodium EDTA.

One embodiment of the invention contains, in addition to the meglumineor sodium salt of meloxicam, polyethyleneglycols, glycofurol and/orpolyoxyethylene-polyoxypropylene copolymers, but particularlypolyethyleneglycols (e.g., Macrogol 300) and/orpolyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer 188) assolubilizer, ethanol, benzoic acid and the sodium or potassium saltsthereof, or sorbic acid and the sodium or potassium salts thereof, butparticularly ethanol, as preservative, and glycine, a mixture ofglycine/HCl, or a mixture of glycine/sodium hydroxide solution, butpreferably glycine, as buffer, and disodium EDTA as an additionalexcipient.

The formulation according to the invention may contain meloxicam in aconcentration of 11-25 mg/mL, preferably 13-24 mg/mL, preferably 16-23mg/mL, particularly preferably 18-22 mg/mL, and especially 20 mg/mL.

The meglumine concentration may be between 12.5 and 16.5 mg/mL,preferably 13-16 mg/mL, preferably 13.5-15.5 mg/mL, more preferably14-15 mg/mL, and especially about 14 mg/mL. The possible sodium,potassium, and ammonium concentrations are calculated accordingly.

The concentration of the solubilizers may be in the range from 20-200mg/mL, preferably 30-150 mg/mL, preferably 40-130 mg/mL, more preferably50-120 mg/mL, and especially 70-100 mg/mL.

The concentration of the preservative ethanol may be in the range from100-200 mg/mL, preferably 120-180 mg/mL, and more preferably about 150mg/mL.

The concentration of the preservatives benzoic acid and the sodium orpotassium salts thereof, sorbic acid and the sodium or potassium saltsthereof, chlorobutanol, benzyl alcohol, phenylethanol, phenol, m-cresol,and p-chloro-m-cresol, may be in the range from 0.5-50 mg/mL, preferably1-10 mg/mL, and more preferably 3-5 mg/mL.

The concentration of the preservatives benzalkonium chloride,phenylmercury nitrate, and methyl, ethyl, propyl, orbutyl-p-hydroxybenzoates, may be in the range from 0.01-4 mg/mL,preferably 0.02-3 mg/mL, and more preferably 0.1-0.5 mg/mL.

The concentration of the buffer substances may be between 4 and 50mg/mL, preferably between 5 and 20 mg/mL, and more preferably between 8and 10 mg/mL.

The concentration of the other excipients mentioned above, e.g., EDTA,citric acid, lecithin, gluconic acid, tartaric acid, and phosphoric acidor the salts thereof, may be in the range from 0.2-3 mg/mL, preferably0.3-2.5 mg/mL, preferably 0.5-2 mg/mL, most preferably 0.6-1.5 mg/mL,and in particular 0.7-1.0 mg/mL.

Meglumine and meloxicam may be used in a molar ratio of between 9:8 and12:8, preferably in a molar ratio of 11:8, but especially in a molarratio of 10:8.

In the formulation according to the invention, meloxicam and the otherexcipient, particularly disodium EDTA, may be present in a weight ratioof between 25:1 and 15:1, preferably between 24:1 and 16:1, preferablybetween 23:1 and 17:1, more preferably between 22:1 and 18:1, mostpreferably between 21:1 and 19:1, and in particular about 20:1.

The formulation according to the invention may have shelf-life afteropening of 28 days or more.

The shelf-life of the solution in the sealed original packaging may be 1month or more, in particular between 1 month and 24 months, but at leastbetween 1 month and 18 months, preferably between 1 month and 12 months,more preferably between 1 month and 9 months, most preferably between 1month and 6 months, particularly between 1 month and 3 months. Detailsof the stability tests by way of example can be found in Tables 1 and 2which follow:

Test of Stability After Opening

Packing material: 50 mL colorless glass vials, glass type I,ethylenepropylenenorbornene terpolymer rubber stopper (Type: WI 640grey), aluminium flanged cap.

Recipe: analogous to Example 1 of the description

4 mL samples were taken from the storage samples three times a day forsix days and on the seventh day 4 mL samples were taken four times.Storage was then continued until 28 days had elapsed and samples weretaken again. TABLE 1 Test Storage conditions Storage time Meloxicamcontent No. [° C./% relative humidity] [Days] [mg/mL] 1 25° C. 0 19.725° C./60% 28 19.2 2 25° C. 0 20 25° C./60% 28 19.2

In both samples, in addition to the meloxicam content, the parametersinvestigated, namely appearance (clear yellow solution), pH (8.0-9.7),ethanol content (13.5-15.75), disodium EDTA content (85.0-110.0 mg/100mL), sterility (according to Pharm. Eur. and USP), and the stability ofthe packaging material were found to be unchanged.

Long Term Stability Test in Sealed Original Packaging

Packaging material: 50 mL colorless glass vials, glass type I,ethylenepropylenenorbornene terpolymer rubber stopper (Type: WI 640grey), aluminium flanged cap.

Recipe: Analogous to Example 1 of the description. TABLE 2 Test Storageconditions Storage time Meloxicam content No. [° C./% relative humidity][Days] [mg/mL] 1 25° C. 0 19.7  4° C. 6 19.9 40° C./75% 6 19.5 25°C./60% 18 19.3 30° C./70% 18 19.4 2 25° C. 0 20.0  4° C. 6 19.9 40°C./75% 6 19.7 25° C./60% 18 19.4 30° C./70% 18 19.5 25° C./60% 24 19.530° C./70% 24 19.5

In both samples, in addition to the meloxicam content, the parametersinvestigated, namely appearance (clear yellow solution), pH (8.0-9.7),ethanol content (13.5-15.75), disodium EDTA content (85.0-110.0 mg/100mL), sterility (according to Pharm. Eur. and USP), and the stability ofthe packaging material were found to be unchanged.

The formulation according to the invention should have a pH of between 8and 10, preferably between 8.5 and 9, more preferably a pH between 8.7and 8.9, and particularly 8.8.

The formulation according to the invention is suitable for treatingpain, inflammation, fever, acute mastitis, diarrhea, lameness, problemswith the locomotor apparatus, and respiratory complaints in animals,preferably acute mastitis, diarrhea, lameness, problems with thelocomotor apparatus and respiratory complaints, especially acutemastitis, diarrhea, lameness, problems with the locomotor apparatus andrespiratory complaints, and most preferably respiratory complaints. Thetreatment may be given in conjunction with antibiotic therapy.

The formulation according to the invention is suitable for treatinganimals, preferably farm animals, and more particularly large farmanimals.

The formulation according to the invention is suitable for treatinganimals, preferably animals up to 500 kg, particularly large animals upto 750 kg.

The dosage of the formulation according to the invention shouldcorresponding to 0.2 to 1.0 mg of active substance per kg of bodyweight,preferably 0.4 to 0.8 mg/kg of bodyweight, more preferably 0.5 to 0.7mg/kg of bodyweight, and particularly preferably 0.6 mg/kg ofbodyweight.

The formulation according to the invention may be prepared using themethods of preparing aqueous liquid formulations known from theliterature. For example, the appropriate excipients may be added to ameloxicam salt solution.

Various commercial materials for aqueous liquid formulations which willallow sealing under inert gas and final sterilization by autoclaving inthe finished container may be used as a packaging material for theformulation according to the invention. Such materials include forexample ampoules or glass vials, particularly glass vials, e.g., 50 mLor 100 mL glass vials of glass Type I (according to Pharm. Eur/USP) inconjunction with rubber stoppers made of ethylenepropylenenorborneneterpolymer (Type WI 640 grey) and aluminium caps.

The meloxicam solutions according to the invention will now beillustrated by the Examples which follow. Anyone skilled in the art willbe aware that the Examples serve only as an illustration and are not tobe regarded as restrictive.

EXAMPLES

Example 1: 2% Meloxicam Solution Component Amount (g/L) Meloxicam 20.0Meglumine 14.0 Macrogol 300¹ 150.0 Poloxamer 188² 50.0 Ethanol 150.0Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1M NaOH q.s. ad pH 8.8Water for injections ad 1000 mLLegend:¹obtainable from Brenntag, Plochingen, Germany; and²obtainable from C. H. Erbsloeh, Krefeld, Germany

Method:

20 g of meloxicam are dissolved in 500 mL of an aqueous megluminesolution (14 g/500 mL) at 90° C. The other excipients are added oneafter another to the solution according to the recipe given above. A pHof 8.8 is then achieved using 1M hydrochloric acid and 1M sodiumhydroxide solution. Water is added to the solution until a volume of 1liter is obtained. Example 2: 2% Meloxicam Solution Component Amount(g/L) Meloxicam 20.0 Meglumine 12.5 PEG 400 100.0 Poloxamer 50.0 Ethanol150.0 Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1M NaOH q.s. ad pH8.8 Water for injections ad 1000 mL

Method:

20 g of meloxicam are dissolved in 500 mL of an aqueous megluminesolution (12.5 g/500 mL) at 90° C. The other excipients are added oneafter another to the solution according to the recipe given above. A pHof 8.8 is then achieved using 1M hydrochloric acid or 1M sodiumhydroxide solution. Water is added to the solution until a volume of 1liter is obtained. Example 3: 2.5% Meloxicam Solution Component Amount(g/L) Meloxicam 25.0 Meglumine 17.5 PEG 300 150.0 Poloxamer 50.0 Ethanol150.0 Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1M NaOH q.s. ad pH8.8 Water for injections ad 1000 mL

Method:

25 g of meloxicam are dissolved in 500 mL of an aqueous megluminesolution (17.5 g/500 mL) at 90° C. The other excipients are added oneafter another to the solution according to the recipe given above. A pHof 8.8 is then achieved using 1M hydrochloric acid or 1M sodiumhydroxide solution. Water is added to the solution until a volume of 1liter is obtained. Example 4: 1.5% Meloxicam Solution Component Amount(g/L) Meloxicam 15.0 Meglumine 10.5 PEG 300 100.0 Poloxamer 50.0 Ethanol150.0 Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1M NaOH q.s. ad pH8.8 Water for injections ad 1000 mL

Method:

15 g of meloxicam are dissolved in 500 mL of an aqueous megluminesolution (10.5 g/500 mL) at 90° C. The other excipients are added oneafter another to the solution according to the recipe given above. A pHof 8.8 is then achieved using 1M hydrochloric acid or 1M sodiumhydroxide solution. Water is added to the solution until a volume of 1liter is obtained. Example 5: 2% Meloxicam Solution Component Amount(g/L) Meloxicam 20.0 Meglumine 14.0 PEG 300 150.0 Poloxamer 50.0p-Chloro-m-cresol 2.0 Glycine 5.0 EDTA-Na 1.0 1M HCl q.s. ad pH 8.8 1MNaOH q.s. ad pH 8.8 Water for injections ad 1000 mL

Method:

20 g of meloxicam are dissolved in 500 mL of an aqueous megluminesolution (14 g/500 mL) at 90° C. The other excipients are added oneafter another to the solution according to the recipe given above. A pHof 8.8 is then achieved using 1M hydrochloric acid or 1M sodiumhydroxide solution. Water is added to the solution until a volume of 1liter is obtained.

1. An aqueous cyclodextrin-free solution of meloxicam for administrationby oral or parenteral route, comprising a pharmacologically acceptablemeloxicam salt of an organic or inorganic base and one or more suitableexcipients, wherein the concentration of dissolved meloxicam salt ismore than 10 mg/mL.
 2. The aqueous solution according to claim 1,wherein the meloxicam salt is the sodium or meglumine salt.
 3. Theaqueous solution according to claim 2, wherein the solution containsmeglumine and meloxicam in a molar ratio of between 9:8 and 12:8.
 4. Theaqueous solution according to claim 3, wherein the solution containsmeglumine and meloxicam in a molar ratio of 10:8.
 5. The aqueoussolution according to one of claims 1 to 4, wherein the one or moresuitable excipients is selected from the group consisting a buffer and apreservative.
 6. The aqueous solution according to claim 5, wherein thepreservative is selected from the group consisting of ethanol; benzoicacid and the sodium and potassium salts thereof; sorbic acid and thesodium and potassium salts thereof; chlorobutanol; benzyl alcohol;phenylethanol; the methyl, ethyl, propyl, and butyl p-hydroxybenzoates;phenol; m-cresol; p-chloro-m-cresol; phenylmercury nitrate; andbenzalkonium chloride.
 7. The aqueous solution according to claim 5,wherein the buffer is selected from the group consisting of: glycine; amixture of glycine and HCl; a mixture of glycine and sodium hydroxidesolution, and the sodium and potassium salts thereof; a mixture ofpotassium hydrogen phthalate and hydrochloric acid; a mixture ofpotassium hydrogen phthalate and sodium hydroxide solution; and amixture of glutamic acid and glutamate.
 8. The aqueous solutionaccording to one of claims 1 to 4, wherein the one or more suitableexcipients includes a solubilizer.
 9. The aqueous solution according toclaim 8, wherein the solubilizer is selected from the group consistingof: polyethyleneglycols, polyoxyethylene-polyoxypropylene copolymers,glycofurol, arginine, lysine, castor oil, propyleneglycol, solketal,polysorbate, glycerol, sorbitol, mannitol, xylitol,polyvinylpyrrolidone, lecithin, cholesterol, 12-hydroxystearicacid-PEG660-ester, propyleneglycol monostearate, polyoxy-40-hydrogenatedcastor oil, polyoxyl-10-oleyl-ether, polyoxyl-20-cetostearylether,polyoxyl-40-stearate, and mixtures thereof.
 10. The aqueous solutionaccording to one of claims 1 to 4, wherein the one or more suitableexcipients is selected from the group consisting of: citric acid,lecithin, gluconic acid, tartaric acid, phosphoric acid, and EDTA andthe alkali metal salts thereof.
 11. The aqueous solution according toone of claims 1 to 4, wherein the shelf-life of the solution afteropening is 28 days or more at ambient temperature.
 12. The aqueoussolution according to claim 5, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 13. The aqueoussolution according to claim 6, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 14. The aqueoussolution according to claim 7, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 15. The aqueoussolution according to claim 8, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 16. The aqueoussolution according to claim 9, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 17. The aqueoussolution according to claim 10, wherein the shelf-life of the solutionafter opening is 28 days or more at ambient temperature.
 18. The aqueoussolution according to one of claims 1 to 4, wherein the solution has along term shelf-life of 24 months or more at ambient temperature in itsoriginal packaging.
 19. The aqueous solution according to claim 5,wherein the solution has a long term shelf-life of 24 months or more atambient temperature in its original packaging.
 20. The aqueous solutionaccording to claim 6, wherein the solution has a long term shelf-life of24 months or more at ambient temperature in its original packaging. 21.The aqueous solution according to claim 7, wherein the solution has along term shelf-life of 24 months or more at ambient temperature in itsoriginal packaging.
 22. The aqueous solution according to claim 8,wherein the solution has a long term shelf-life of 24 months or more atambient temperature in its original packaging.
 23. The aqueous solutionaccording to claim 9, wherein the solution has a long term shelf-life of24 months or more at ambient temperature in its original packaging. 24.The aqueous solution according to claim 10, wherein the solution has along term shelf-life of 24 months or more at ambient temperature in itsoriginal packaging.
 25. The aqueous solution according to one of claims1 to 4, wherein the solution has a pH of between 8.0 and
 10. 26. Theaqueous solution according to claim 1, comprising meloxicam, meglumine,a polyethyleneglycol, a polyoxyethylene-polyoxypropylene copolymer,ethanol, glycine, disodium EDTA, and optionally sodium hydroxide orhydrochloric acid.
 27. The aqueous solution according to claim 1,consisting essentially of meloxicam, meglumine, a polyethyleneglycol, apolyoxyethylene-polyoxypropylene copolymer, ethanol, glycine, disodiumEDTA, water suitable for injection, and optionally sodium hydroxide orhydrochloric acid.
 28. A method of treating pain, inflammation, fever,acute mastitis, diarrhea, lameness, problems with the locomotorapparatus, or respiratory complaints in a mammal, the method comprisingadministering to a mammal in need of such treatment the aqueous solutionaccording to claim
 1. 29. The method according to claim 28, wherein themethod is used in conjunction with antibiotic therapy.
 30. The methodaccording to claim 28, wherein the solution according to claim 1 isadministered in dosage range of from 0.2 to 1.0 mg of activesubstance/kg of bodyweight of the mammal.
 31. The method according toclaim 30, wherein the solution according to claim 1 is administered indosage range of from 0.4 to 0.8 mg of active substance/kg of bodyweightof the mammal.
 32. The method according to claim 30, wherein thesolution according to claim 1 is administered in dosage range of from0.5 to 0.7 mg of active substance/kg of bodyweight of the mammal.